The present invention relates to tetrahydroisoquinoline analogs which are chemokine receptor modulators, and to methods for treating inflammatory diseases such as asthma, constrictive obstructive pulmonary disease (COPD), inflammatory bowel syndrome, allergic diseases, psoriasis, and arthritis.
Chemokines are chemotactic cytokines that are released by a variety of cell types to attract and activate other cell types such as macrophages, T and B lymphocytes, basophils, neutrophils, mast cells, and eosinophils. They are broadly classified as C, CC, CXC, or CX3C chemokines dependent upon their amino acid sequence. For example, in CC chemokines the first two cysteines in the sequence are adjacent, while in CXC chemokines these cysteines are separated by one or more amino acid residues.
Chemokines bind to specific cell-surface receptors that belong to the family of G protein coupled seven transmembrane domain proteins. Upon ligand binding, chemokine receptors transduce an intracellular signal through the associated trimeric G proteins, resulting in calcium flux, changes in cell morphology, upregulated expression of cellular adhesion molecules, degranulation, and promotion of cell migration.
Chemokine receptors are implicated as key mediators of inflammatory, infectious, and immunoregulatory disorders and diseases, including asthma, COPD, and allergic diseases; rheumatoid arthritis, atherosclerosis, and psoriasis; solid organ transplant rejection, osteoarthritis, and inflammatory bowel syndrome. To illustrate, the CCR3 receptor appears to be a key mediator in attracting eosinophils and Th2 polarized CD4+ T cells to sites of inflammation in the lung, and also plays an important role in activating these cells. The ligands that bind CCR3 can induce a rapid increase in the intracellular calcium ion concentration (calcium flux), degranulation, increased expression of cell adhesion molecules, and cell migration. Agents that could modulate activity of the CCR3 receptor would have utility in the treatment of disorders and diseases in which eosinophils or Th2 CD4+ T cells appear to play a prominent role. A similar utility has been demonstrated using antibodies specific for the murine CCR3 chemokine receptor. Such antibodies can be used to deplete eosinophils in in vivo inflammatory models in mice.
Several mammalian viruses such as, but not limited to, cytomegaloviruses, herpesviruses, and poxviruses have been shown to express proteins with the binding properties of chemokine receptors in infected cells. In addition, several chemokine receptors have been demonstrated to act as cellular receptors for a variety of viruses, as well as some bacteria, and parasites. Thus, agents which modulate chemokine receptor activity may also have utility in infectious diseases. Examples would include, but not be limited to, blocking of HIV infection of CCR3, CCR5, or CXCR4 expressing cells; or in the prevention of manipulation of the immune response by viruses such as cytomegaloviruses that use a chemokine receptor for cellular infection.
In accordance with the present invention tetrahydroisoquinoline analogs are provided which are chemokine receptor modulators (especially modulators of CCR3) and have the structure 
wherein R1 is alkyl, aryl, alkenyl, alkynyl, arylalkyl, arylalkenyl, cycloalkyl, arylcycloalkyl cycloalkylalkyl, cycloalkyl-alkoxy, alkoxyalkyl, alkylthioalkyl, aryloxyalkyl, arylalkoxyalkyl, cycloheteroalkyl, cycloheteroalkylalkyl, heteroaryl, or heteroarylalkyl, and where these groups may be optionally substituted with 1 to 3 J1 groups which may be the same or different and the R1 aryls may be further optionally substituted with 1 to 5 halogens, aryl, xe2x80x94CF3, xe2x80x94OCF3, 1-3 hydroxyls, 2 of which substituents where possible, may be joined by a methylene bridge;
R2 is H, alkyl, aryl, alkenyl, alkynyl, arylalkyl, arylalkenyl, cycloalkyl, cycloalkylalkyl, alkoxyalkyl, aryloxyalkyl, arylalkoxyalkyl, cycloheteroalkyl, cycloheteroalkylalkyl, cycloalkylalkoxy, heteroaryl, or heteroarylalkyl, and where these groups may be optionally substituted with a J1a group and the aryls may be further optionally substituted with 1 to 5 halogens, xe2x80x94CF3, xe2x80x94OCF3, or 1-3 hydroxyls;
X is a bond, xe2x80x94Oxe2x80x94, or xe2x80x94NR4xe2x80x94;
R3 and R3a are the same or different and are independently selected from H, alkoxy, halogen, xe2x80x94CF3, alkyl, or aryl;
R4, R4a, R4b, R4c, R4d, R4e, R4f, R4g, R4h, R4i, R4j, R4k, and R4l are the same or different and are independently selected from H, C1-C6alkyl, or aryl;
m, n and p are the same or different and are independently 0 or 1;
Y is a bond, 
where x and y are the same or different and are independently 0 to 3 and z is 1 to 3;
R5 and R5a are the same or different and are independently H, alkyl, alkoxy, hydroxyl, halogen, xe2x80x94CF3, aryl, alkaryl, and cycloalkyl; or R5 and R5a can be independently joined to one or both of R6 and R7 groups (see X2) to form an alkylene bridge of 1 to 5 carbon atoms; or R5 and R5a can be joined together to form a ring of from 4-7 carbon atoms;
X2 is aryl optionally substituted with 1 to 3 J1 groups which may be the same or different, cycloheteroalkyl optionally substituted with 1 to 3 J1 groups which may be the same or different, pyridinyl optionally substituted with 1 to 3 J1 groups which may be the same or different, 
R6 and R7 are the same or different and are independently H or alkyl where the alkyl may be optionally substituted with halogen, 1 to 3 hydroxys, 1 to 3 C1-C10alkanoyloxy, 1 to 3 C1-C6 alkoxy, phenyl, phenoxy, or C1-6alkoxycarbonyl; or R6 and R7 can together form xe2x80x94(CH2)tX5(CH2)uxe2x80x94 where X5 is xe2x80x94C(R4c)(R4d)xe2x80x94, xe2x80x94C(R4c)(NT1T1a)xe2x80x94, xe2x80x94Oxe2x80x94 or xe2x80x94N(R4e)xe2x80x94, t and u are the same or different and are independently 0 to 4;
R8 is H, C1-C6alkyl, xe2x80x94CF3, alkaryl, or aryl, and with the alkyl and aryl groups being optionally substituted with 1 to 3 hydroxys, 1 to 3 C1-C10alkanoyloxy, 1 to 3 C1-C6 alkoxy, phenyl, phenoxy or C1-C6alkoxycarbonyl;
R9 and R10 are the same or different and are independently H, C1-C6alkyl, xe2x80x94CF3, alkaryl, aryl, or halogen, and with the alkyl and aryl groups being optionally substituted with 1 to 3 hydroxys, 1 to 3 C1-C10 alkanoyloxy, 1 to 3 C1-6 alkoxy, phenyl, phenoxy or C1-C6 alkoxycarbonyl;
X3 is a bond, xe2x80x94C(O)xe2x80x94, xe2x80x94C(O)Oxe2x80x94, xe2x80x94C(O)N(R4f)xe2x80x94, xe2x80x94S(O)2xe2x80x94, or xe2x80x94S(O)2N(R4f)xe2x80x94;
X4 is a bond, xe2x80x94Oxe2x80x94, xe2x80x94OC(O)xe2x80x94, xe2x80x94N(R4g)xe2x80x94, xe2x80x94N(R4g)C(O)xe2x80x94, xe2x80x94N(R4g)C(O)N(R4h)xe2x80x94, xe2x80x94N(R4g)S(O)2xe2x80x94, xe2x80x94N(R4g)S(O)2N(R4h), xe2x80x94OC(O)N(R4g)xe2x80x94, xe2x80x94C(O)xe2x80x94, xe2x80x94C(O)N(R4g)xe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94S(O)2xe2x80x94, or xe2x80x94S(O)2N(R4g)xe2x80x94;
J1 and J1a are the same or different and are independently nitro, halogen, hydroxyl, xe2x80x94OCF1, xe2x80x94CF3, alkyl, aryl, xe2x80x94(CH2)vCN, xe2x80x94(CH2)vN(T1a)C(O)T1, xe2x80x94(CH2)vN(T1a)C(O)OT1, xe2x80x94(CH2)vN(T1a)C(O)N(T1a)T1, xe2x80x94(CH2)vNT1(T1a) xe2x80x94(CH2)vN(T1a)SO2T1, xe2x80x94(CH2)vC(O)N(T1a)T1, xe2x80x94(CH2)vC(O)OT1, xe2x80x94(CH2)vOC(O)OT1, xe2x80x94(CH2)vOC(O)T1, xe2x80x94(CH2)vOC(O)OT1, xe2x80x94(CH2)vOC(O)T1, xe2x80x94(CH2)vOC(O)N(T1a)T1, xe2x80x94(CH2)vN(T1a)SO2N(T1b)T1, xe2x80x94(CH2)vOT1, xe2x80x94(CH2)vSO2T1, xe2x80x94(CH2)vSO2N(T1a)T1, xe2x80x94(CH2)vC(O)T1, xe2x80x94(CH2)vCH(OH)T1, or heteroaryl as defined below, with v being 0-3;
T1, T1a and T1b are the same or different and are independently H, alkyl, alkenyl, alkynyl, lower alkythioalkyl, alkoxyalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloheteroalkyl, or cycloalkyl, each of which may be optionally substituted with halogen, hydroxyl, xe2x80x94C(O)NR4iR4j, xe2x80x94NR4iC(O)R4j, xe2x80x94CN, xe2x80x94N(R4i)SO2R11, xe2x80x94OC(O)R4i, xe2x80x94SO2 NR4iR4j, xe2x80x94SOR11, xe2x80x94SO2R11, alkoxy, xe2x80x94COOH, cycloheteroalkyl, or xe2x80x94C(O)OR11; with the proviso that T1 cannot be hydrogen when it is connected to sulfur, as in SO2T1; or T1 and T1a or T1 and T1bcan together form xe2x80x94(CH2)rX5a(CH2)sxe2x80x94 where X5a is xe2x80x94C(R4k)(R4l)xe2x80x94, xe2x80x94C(R4k)(NT1T1a)xe2x80x94, xe2x80x94Oxe2x80x94 or xe2x80x94N(R4k)xe2x80x94, r and s are the same or different and are independently 0 to 4;
R11 is C1-C6alkyl or aryl;
or a pharmaceutically acceptable salt thereof, or a prodrug ester thereof, and including all stereoisomers thereof;
(1) with the proviso that where m is 0 and n is 1, the moiety xe2x80x94X4xe2x80x94R2 is other than alkyl or alkoxy and
(2) where X is a bond and X2 is amino, then m is 1.
Thus, the compounds of formula I of the invention include compounds of the following structures. 
The compounds of the instant invention all have at least one asymmetric center as noted by the asterisk in structural formula I. Additional asymmetric centers may be present on the molecule depending upon the nature of the various substituents on the molecule. Each such asymmetric center will produce two optical isomers and it is intended that all such optical isomers, as separated, pure or partially purified optical isomers or racemic mixtures thereof, be included within the ambit of the instant invention. The racemic mixtures may be separated into individual optical isomers employing conventional procedures such as by chromatography or fractional crystallization. In the case of the asymmetric center represented by the asterisk in formula I, it has been found that compounds with either the R or S configuration are of almost equal activity. Therefore one isomer might be only slightly preferred, therefore both are claimed.
The pharmaceutically acceptable salts of the compounds of formula I of the invention include alkali metal salts such as lithium, sodium or potassium, alkaline earth metal salts such as calcium or magnesium, as well as zinc or aluminum and other cations such as ammonium, choline, diethanolamine, ethylenediamine, t-butylamine, t-octylamine, dehydroabietylamine, as well as pharmaceutically acceptable anions such as chloride, bromide, iodide, tartrate, acetate, methanesulfonate, maleate, succinate, glutarate, and salts of naturally occurring amino acids such as arginine, lysine, alanine and the like, and prodrug esters thereof.
In addition, in accordance with the present invention, a method for increasing levels of endogenous growth hormone or increasing the endogenous production or release of growth hormone is provided wherein a compound of formula I as defined hereinbefore is administered in a therapeutically effective amount.
Furthermore, in accordance with the present invention, a method is provided for preventing or treating osteoporosis (improving bone density and/or strength), or treating obesity, or increasing muscle mass and/or muscle strength, or maintenance of muscle strength and function in elderly humans, or reversal or prevention of fraility in elderly humans, wherein a compound of formula I as defined hereinbefore is administered in a therapeutically effective amount.
The following definitions apply to the terms as used throughout this specification, unless otherwise limited in specific instances.
Unless otherwise indicated, the term xe2x80x9clower alkylxe2x80x9d, xe2x80x9calkylxe2x80x9d or xe2x80x9calkxe2x80x9d as employed herein alone or as part of another group includes both straight and branched chain hydrocarbons, containing 1 to 40 carbons, preferably 1 to 20 carbons, more preferably 1 to 6 carbons, in the normal chain, such as methyl, ethyl, propyl, isopropyl, butyl, t-butyl, isobutyl, pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl, 2,2,4-trimethylpentyl, nonyl, decyl, undecyl, dodecyl, the various branched chain isomers thereof, and the like as well as such groups including 1 to 3 substituents including alkyl, aryl, alkenyl, alkynyl, hydroxy, arylalkyl, cycloalkyl, cycloalkylalkyl, alkoxy, arylalkyloxy, alkanoyl, amino, haloaryl, CF3, OCF3, aryloxy, heteroaryl, cycloalkylalkoxyalkyl, or cycloheteroalkyl.
Unless otherwise indicated, the term xe2x80x9ccycloalkylxe2x80x9d as employed herein alone or as part of another group includes saturated or partially unsaturated (containing 1 or 2 double bonds) cyclic hydrocarbon groups containing 1 to 3 rings, including monocyclicalkyl, bicyclicalkyl and tricyclicalkyl, containing a total of 3 to 20 carbons forming the rings, preferably 3 to 7 carbons, forming the ring and which may be fused to 1 or 2 aromatic rings as described for aryl, which include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl, cyclododecyl, cyclohexenyl, 
any of which groups may be optionally substituted with 1 to 3 substituents as defined above for alkyl.
The term xe2x80x9carylxe2x80x9d as employed herein alone or as part of another group refers to monocyclic and bicyclic aromatic groups containing 6 to 10 carbons in the ring portion (such as phenyl or naphthyl) and may optionally include one to three additional rings fused to xe2x80x9carylxe2x80x9d (such as aryl, cycloalkyl, heteroaryl or cycloheteroalkyl rings) and may be optionally substituted through available carbon atoms with 1 to 5 halo, 1, 2, or 3 groups selected from hydrogen, haloalkyl, alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, trifluoromethyl, trifluoromethoxy, alkynyl, cycloalkylalkyl, fluorenyl, cycloheteroalkyl, cycloheteroalkylalkyl, aryl, heteroaryl, arylalkyl, aryloxy, aryloxyalkyl, arylalkoxy, arylthio, arylazo, heteroarylalkyl, heteroarylalkenyl, heteroarylheteroaryl, heteroaryloxy, hydroxy, nitro, oxo, cyano, amino, substituted amino wherein the amino includes 1 or 2 substituents (which are alkyl, aryl or any of the other aryl compounds mentioned in the definitions), thiol, alkylthio, arylthio, heteroarylthio, arylthioalkyl, alkoxyarylthio, alkylcarbonyl, arylcarbonyl, alkylaminocarbonyl, arylaminocarbonyl, alkoxycarbonyl, aminocarbonyl, alkylcarbonyloxy, arylcarbonyloxy, alkylcarbonylamino, arylcarbonylamino, arylsulfinyl, arylsulfinylalkyl, arylsulfonylamino or arylsulfonaminocarbonyl, or preferably any of the aryl substituents as set out above.
Preferred aryl groups include phenyl, biphenyl or naphthyl.
The term xe2x80x9caralkylxe2x80x9d, xe2x80x9caryl-alkylxe2x80x9d or xe2x80x9caryllower alkylxe2x80x9d as used herein alone or as part of another group refers to alkyl groups as discussed above having an aryl substituent, such as benzyl or phenethyl, or naphthylpropyl, or an aryl as defined above.
The term xe2x80x9clower alkoxylxe2x80x9d, xe2x80x9calkoxylxe2x80x9d, xe2x80x9caryloxylxe2x80x9d or xe2x80x9caralkoxyxe2x80x9d as employed herein alone or as part of another group includes any of the above alkyl, aralkyl or aryl groups linked to an oxygen atom.
The term xe2x80x9caminoxe2x80x9d as employed herein alone or as part of another group may optionally be substituted with one or two substituents such as alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloheteroalkyl, cycloheteroalkylalkyl and/or cycloalkyl.
The term xe2x80x9clower alkylthioxe2x80x9d, xe2x80x9calkylthioxe2x80x9d, xe2x80x9calkylthioalkylxe2x80x9d, xe2x80x9carylthioxe2x80x9d or xe2x80x9caralkylthioxe2x80x9d as employed herein alone or as part of another group includes any of the above alkyl, aralkyl or aryl groups linked to a sulfur atom.
The term xe2x80x9clower alkylaminoxe2x80x9d, xe2x80x9calkylaminoxe2x80x9d, xe2x80x9carylaminoxe2x80x9d, or xe2x80x9carylalkylaminoxe2x80x9d as employed herein alone or as part of another group includes any of the above alkyl, aryl or arylalkyl groups linked to a nitrogen atom.
The term xe2x80x9cacylxe2x80x9d as employed herein by itself or part of another group, as defined herein, refers to an organic radical linked to a carbonyl 
group; examples of acyl groups include alkanoyl, alkenoyl, aroyl, aralkanoyl, heteroaroyl, cycloalkanoyl, and the like.
The term xe2x80x9calkanoylxe2x80x9d as used herein alone or as part of another group refers to alkyl linked to a carbonyl group.
Unless otherwise indicated, the term xe2x80x9clower alkenylxe2x80x9d or xe2x80x9calkenylxe2x80x9d as used herein by itself or as part of another group refers to straight or branched chain radicals of 2 to 20 carbons, preferably 3 to 12 carbons, and more preferably 2 to 6 carbons in the normal chain, which include one to six double bonds in the normal chain, such as vinyl, 2-propenyl, 3-butenyl, 2-butenyl, 4-pentenyl, 3-pentenyl, 2-hexenyl, 3-hexenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 3-octenyl, 3-nonenyl, 4-decenyl, 3-undecenyl, 4-dodecenyl, 4,8,12-tetradecatrienyl, and the like, and which may be optionally substituted with 1 to 4 substituents, namely, halogen, haloalkyl, alkyl, alkoxy, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, amino, hydroxy, heteroaryl, cycloheteroalkyl, alkanoylamino, alkylamido, arylcarbonylamino, nitro, cyano, thiol, alkylthio or any of the substituents for alkyl as set out herein.
Unless otherwise indicated, the term xe2x80x9clower alkynylxe2x80x9d or xe2x80x9calkynylxe2x80x9d as used herein by itself or as part of another group refers to straight or branched chain radicals of 2 to 20 carbons, preferably 2 to 12 carbons and more preferably 2 to 8 carbons in the normal chain, which include one triple bond in the normalchain, such as 2-propynyl, 3-butynyl, 2-butynyl, 4-pentynyl, 3-pentynyl, 2-hexynyl, 3-hexynyl, 2-heptynyl, 3-heptynyl, 4-heptynyl, 3-octynyl, 3-nonynyl, 4-decynyl,3-undecynyl, 4-dodecynyl and the like, and which may be optionally substituted with 1 to 4 substituents, namely, halogen, haloalkyl, alkyl, alkoxy, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, amino, heteroaryl, cycloheteroalkyl, hydroxy, alkanoylamino, alkylamido, arylcarbonylamino, nitro, cyano, thiol, and/or alkylthio, or any of the substituents for alkyl as set out herein.
The term xe2x80x9calkylenexe2x80x9d as employed herein alone or as part of another group refers to alkyl groups as defined above having single bonds for attachment to other groups at two different carbon atoms and may optionally be substituted as defined above for xe2x80x9calkylxe2x80x9d.
The terms xe2x80x9calkenylenexe2x80x9d and xe2x80x9calkynylenexe2x80x9d as employed herein alone or as part of another group refer to alkenyl groups as defined above and alkynyl groups as defined above, respectively, having single bonds for attachment at two different carbon atoms.
Examples of (CH2)m, (CH2)n, (CH2)p, (CH2)r, (CH2)s, (CH2)t, CH2)u, (CH2)v, (CH2)x, (CH2)y, (CH2)z, and other groups (which may include alkylene, alkenylene or alkynylene groups as defined herein, and may optionally include 1, 2, or 3 substituents which may be any of the substituents for alkyl set out herein), are as follows: 
The term xe2x80x9chalogenxe2x80x9d or xe2x80x9chaloxe2x80x9d as used herein alone or as part of another group refers to chlorine, bromine, fluorine, and iodine as well as CF3, with chlorine or fluorine being preferred.
The term xe2x80x9cmetal ionxe2x80x9d refers to alkali metal ions such as sodium, potassium or lithium and alkaline earth metal ions such as magnesium and calcium, as well as zinc and aluminum.
The term xe2x80x9cheterocyclicxe2x80x9d, xe2x80x9cheterocycloxe2x80x9d or xe2x80x9cheterocyclexe2x80x9d as employed herein alone or as part of another group refers to xe2x80x9cheteroarylxe2x80x9d groups or xe2x80x9ccycloheteroalkylxe2x80x9d groups.
The term xe2x80x9ccycloheteroalkylxe2x80x9d as used herein alone or as part of another group refers to a 4-, 5-, 6- or 7-membered saturated or partially unsaturated ring which includes 1 to 2 hetero atoms such as nitrogen, oxygen and/or sulfur, linked through a carbon atom or a heteroatom, where possible, optionally via the linker (CH2)p (which is defined above), such as 
and the like. The above groups may include 1 to 4 substituents such as alkyl, halo, oxo and/or any of of the aryl substituents set out herein. In addition, any of the above rings can be fused to a cycloalkyl, aryl, heteroaryl or cycloheteroalkyl ring.
The term xe2x80x9cheteroarylxe2x80x9d as used herein alone or as part of another group refers to a 5- or 6-membered aromatic ring which includes 1, 2, 3 or 4 hetero atoms such as nitrogen, oxygen or sulfur,and such rings fused to an aryl, cycloalkyl, heteroaryl or cycloheteroalkyl ring (e.g. benzothiophenyl, indolyl), and includes possible N-oxides, such as 
and the like.
The heteroaryl groups may optionally include 1 to 4 substituents such as any of the aryl substituents set out herein as well as carbonyl and arylcarbonyl. In addition, any of the above rings can be fused to a cycloalkyl, aryl, heteroaryl or cycloheteroalkyl ring.
Preferred are compounds of formula IB wherein R1 is alkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, alkoxyalkyl, aryloxyalkyl, heteroaryl, or heteroarylalkyl, and where these groups may be further optionally substituted with a J1 group;
R2 is, alkyl, aryl, arylalkyl, alkoxyalkyl, aryloxyalkyl, heteroaryl, cycloalkyl, cycloalkylalkyl, or heteroarylalkyl, and these groups may be further optionally substituted by J1a;
X is xe2x80x94Oxe2x80x94 or xe2x80x94Nxe2x80x94R4;
R3 and R3a are the same or different and are independently H, alkoxy, halogen, xe2x80x94CF3;
R4 is H or C1-C6 alkyl;
m and n are independently 0 or 1;
Y is 
where x and y are independently 0 to 3;
R5 and R5a are the same or different and are independently H, alkyl, xe2x80x94CF3, or R5 and R5a can be independently joined to one or both of R6 and R7 groups (see X2) to form an alkylene bridge of 1 to 5 carbon atoms;
X2 is 
R6 and R7 are the same or different and are independently H or alkyl, where alkyl can optionally be substituted with halogen, 1 or 2 hydroxyls, 1 or 2 C1-C10 alkanoyloxy, 1 or 2 C1-C6 alkoxy, phenyl, phenoxy, C1-C6 alkoxycarbonyl; or R6 and R7 can together form xe2x80x94(CH2)tX5(CH2)uxe2x80x94 where X5 is C(R4)(R4a) or O, t and u are independently 1-3;
X3 is xe2x80x94C(O)xe2x80x94, xe2x80x94C(O)Oxe2x80x94, or xe2x80x94S(O)2N(R4)
X4 is a bond, xe2x80x94Oxe2x80x94, xe2x80x94OC(O)xe2x80x94, or xe2x80x94N(R4)C(O)xe2x80x94;
J1 is xe2x80x94(CH2)vCN, xe2x80x94(CH2)vN(T1a)C(O)T1, xe2x80x94(CH2)vN(T1a)C(O)OT1, xe2x80x94(CH2)vN(T1a)C(O)N(T1b)T1, xe2x80x94(CH2)vSO2T1, xe2x80x94(CH2)vN(T1a)SO2T1, xe2x80x94(CH2)vC(O)vN (T1a) T1, xe2x80x94(CH2)vC(O)OT1, xe2x80x94(CH2)vOC(O)T1, (CH2)vOC(O)N(T1a)T1, xe2x80x94(CH2)vN(T1a)SO2N(T1b)T1, xe2x80x94(CH2)vOT1, xe2x80x94(CH2)vSO2N(T1a)T1, xe2x80x94(CH2)vC(O)T1, or heteroaryl, with v being 0-2;
J1a is halogen, xe2x80x94(CH2)vCN, xe2x80x94(CH2)vN(T1a)C(O)T1, xe2x80x94(CH2)vC(O)N(T1a)T1, xe2x80x94(CH2)vC(O)OT1, xe2x80x94(CH2)vOT1, or xe2x80x94(CH2)vC(O)T1, with v being 0-2;
T1, T1a and T1b are the same or different and are independently H, alkyl, aryl, alkaryl, or cycloalkyl;
each optionally substituted with halogen, hydroxyl or alkoxy; with the proviso that T1 cannot be hydrogen when it is connected to sulfur as in SO2T1;
Most preferred are compounds of the formula IB, wherein R1 is alkyl, aryl, arylakyl, cycloalkyl, and cycloalkylalkyl and where these groups may be further optionally substituted with a J1 group;
R2 is alkyl, aryl, arylalkyl, or cycloalkyl, and these groups may be further optionally substituted by J1a;
X is xe2x80x94NH or xe2x80x94NCH3;
R3 and R3a are each H;
m is 1;
n is 0;
Y is 
where x and y are independently 0 or 1, with the proviso that both cannot be 0;
R5 and R5a are the same or different and are independently H, alkyl, xe2x80x94CF3; or R5 and R5a can be independently joined to one or both of R6 and R7 groups (see X2) to form an alkylene bridge of 1 to 5 carbon atoms;
X2 is 
R6 and R7 are the same or different and are independently H or alkyl where alkyl may be optionally substituted with halogen, or 1 to 2 hydroxyls;
X3 is xe2x80x94C(O)xe2x80x94, xe2x80x94C(O)Oxe2x80x94, or xe2x80x94S(O)2N(R4f);
X4 is xe2x80x94Oxe2x80x94, or xe2x80x94OC(O)xe2x80x94;
J1 is xe2x80x94(CH2)vCN, xe2x80x94(CH2)vN(T1a)C(O)T1, xe2x80x94(CH2)vN(T1a)C(O)OT1, xe2x80x94(CH2)vN(T1a)C(O)N(T1b)T1, xe2x80x94(CH2)vSO2T1, xe2x80x94(CH2)vN(T1a)SO2T1, xe2x80x94(CH2)vC(O)N(T1a)T1, xe2x80x94(CH2)vC(O)OT1, xe2x80x94(CH2)vOC(O)T1, xe2x80x94(CH2)vOC(O)N(T1a)T1, xe2x80x94(CH2)vN(T1a)SO2N(T1b)T1, xe2x80x94(CH2)vOT1, xe2x80x94(CH2)vSO2N(T1a)T1, xe2x80x94(CH2)vC(O)T1, or heteroaryl, with v being 0-2;
J1a is halogen, xe2x80x94(CH2)vCN, xe2x80x94(CH2)vN(T1a)C(O)T1, xe2x80x94(CH2)vC(O)N(T1a)T1, xe2x80x94(CH2)vC(O)OT1, xe2x80x94(CH2)vOT1, or xe2x80x94(CH2)vC(O)T1, with v being 0-2;
T1, T1a and T1b are the same or different and are independently H, alkyl, aryl or alkaryl, each optionally substituted with halogen, hydroxyl or alkoxy; with the proviso that T1 cannot be hydrogen when it is connected to carbonyl or sulfur, as in C(O)T1 or SO2T1;
Examples of preferred compounds of the invention include the following: 
The compounds of the present invention may be prepared according to the following general synthetic schemes, as well as relevant published literature procedures that are used by one skilled in the art. Exemplary reagents and procedures for these reactions appear hereinafter and in the working Examples. Unless otherwise specified, the various substituents of the compounds are defined in the same manner as the formula I compound of the invention.
With respect to the following reaction schemes, amide bond forming reactions are conducted under standard peptide coupling procedures know in the art. Optimally, the reaction is conducted in a solvent such as DMF at 0xc2x0 C. to room temperature using EDAC (WSC) (1-ethyl-3-(dimethyl-aminopropyl)carbodiimide), HOBt(1-hydroxybenzotriazole) or HOAt (1-hydroxy-7-aza-benzotriazole) and a base (Hunigs base). Carbamates of formula IE can be formed under standard conditions known in the art from chloroformates, the piperidine amine and a base.
Tetrahydroisoquinolines can be formed as shown in Scheme 1. Suitable cyclization procedures are described in J. Med. Chem., 87, 1821-1825 (1984), Tet. Lett, 21, 4819 (1980), Synthesis, 824 (1987). Alternative examples are shown in Scheme 8 (J. Org. Chem., 61, 8103-8112 (1996); Tetrahedron, 43, 5095 (1987)), Scheme 9 (Syn. Com. 23, 473-486 (1993); J Chem. Soc., Perkin Trans 1, 2497 (1996); Tet. Lett., 37, 5329 (1996)), and Scheme 10 (Tetrahedron, 50, 6193 (1994); Tet. Lett., 34, 5747-5750 (1993); J Chem Soc, Chem Commun, 11, 966 (1993)) and Scheme 11. The intermediate A in Scheme 8 can be prepared by suitable methods known in the art, such as in Tet. Lett, 37, 5453 (1996) and Synthesis, 824 (1987). The protecting group Pc in Scheme 8 can be chiral (formamidine activation Meyers, A. I., J. Org. Chem., 61, 8103-8112 (1990)), imparting chirality to compounds 48-50. The synthesis outlined in Scheme 10 can also lead to chiral induction in intermediates 66-71. Intermediates 49, 50, 61, 71 and 78 in Schemes 8 to 11 can be further transformed by methods disclosed in Schemes 1-7.
Protection and deprotection in the Schemes below may be carried out by procedures generally known in the art. See, for example, T. W. Greene, Protecting Groups in Organic Synthesis, Second Edition, 1991. P in the Schemes below denotes a nitrogen protecting group, optimally BOC or Cbz. The BOC group can be removed under acidic conditions, optimally HCl or trifluoroacetic acid. The Cbz group can be removed via hydrogenolysis, optimally using a palladium catalyst and hydrogen, or using TMSI. P1 in the Schemes below denotes a phenol protecting group such as BOC (removed by acid or base hydrolysis) or benzyl (removed by hydrogenolysis or TMSI).
Phenol intermediates shown in the General Schemes below may be acylated by methods known in the art to prepare esters and carbamates. The same phenol intermediates may be transformed into anilines by methods known in the art, such as Rossi, J Org Chem, 37 (1972). The anilines may be acylated by methods known in the art to prepare amides, ureas, and other derivatives covered by X4. The same phenol intermediates can be transformed to acids, esters or amides through an activated intermediate, such as triflate, by methods known in the art; phenol to acid: Jutand J Chem Soc., 23, 1729-1730 (1992), Wang Tet. Lett., 37, 6661-6664 (1996); to esters: Fretz Tet. Lett., 37, 8475-8478 (1996), Horikawa Heterocycles, 40, 1009-1014 (1995) ; to amides: Cacchi Tet. Lett., 27, 3931 (1986); to sulfides: Arould Tet. Lett., 37, 4523-4524 (1996), Percec J Org Chem, 60, 6895-6903 (1995), Meier Angew Chem, 106, 493-495 (1994), Wong J Med Chem, 27, 20 (1984). The resulting sulfides can be oxidized to sulfones and sulfoxides by standard methods known in the art, such as meta-chloroperoxybenzoic acid.
The arylation reaction covered in Scheme 2 can be performed under the coupling conditions in the literature described in Evans et al, Tet Lett, 39, 2937-2940 (1998).
Please note that in the following Schemes 1-10 the compounds of formula IB (m=1 and n=0) are shown. However, the schemes are also applicable in preparing all compounds of the formula I invention including compounds of formulae IA, IC and ID of the invention employing reagents or starting materials analogous to those shown in the schemes as will be apparent to one skilled in the art. In the following schemes R2 is other than hydrogen. 
The chemokine receptor modulator compounds of formula I can be administered to animals, including man, to modulate chemokine receptor activity in vivo.
The present invention includes within its scope pharmaceutical compositions comprising, as an active ingredient, at least one of the compounds of formula I in association with a pharmaceutical carrier or diluent. Optionally, the active ingredient of the pharmaceutical compositions can comprise a growth promoting agent in addition to at least one of the compounds of formula I or another composition which exhibits a different activity, e.g., an antibiotic or other pharmaceutically active material.
The compounds of the present invention are agents that are chemokine receptor modulators and can be administered to various mammalian species, such as monkeys, dogs, cats, rats, humans, etc., in need of treatment. These agents can be administered systemically, such as orally or parenterally.
The compounds of the invention can be incorporated in a conventional systemic dosage form, such as a tablet, capsule, elixir or injectable formulation. The above dosage forms will also include the necessary physiologically acceptable carrier material, excipient, lubricant, buffer, antibacterial, bulking agent (such as mannitol), anti-oxidants (ascorbic acid or sodium bisulfite) or the like. Oral dosage forms are preferred, although parenteral, intranasal or aerosol forms are quite satisfactory as well.
The dose administered must be carefully adjusted according to the age, weight, and condition of the patient, as well as the route of administration, dosage form and regimen, and the desired result. In general, the dosage forms described above may be administered in amounts from about 0.0001 to about 100 mg/kg or body weight or in an amount within the range from about 1 to about 1000 mg per day, preferably, from about 5 to about 500 mg per day in single or divided doses of one to four times daily.
The compounds of the present invention may be employed alone or in combination with each other and/or other chemokine receptor modulators or other suitable therapeutic agents useful in the treatment of the aforementioned disorders including: Anti-diabetic agents; anti-osteoporosous agents; anti-obesity agents; anti-inflammatory agents; anti-anxiety agents; anti-depressants; anti-hypertensive agents; anti-platelet agents; anti-thrombotic and thrombolytic agents; cardiac glycosides; cholesterol/lipid lowering agents; mineralocorticoid receptor antagonists; phospodiesterase inhibitors; protein tyrosine kinase inhibitors; thyroid mimetics (including thyroid receptor antagonists); anabolic agents; HIV or AIDS therapies; therapies useful in the treatment of Alzheimer""s disease and other cognitive disorders; therapies useful in the treatment of sleeping disorders; anti-proliferative agents; anti-tumor agents; and/or anti-ulcer and gastroesopheageal reflux disease agents.
Examples of suitable anti-diabetic agents for use in combination with the compounds of the present invention include biguanides (e.g. metformin), glucosidase inhibitors (e.g. acarbose), insulins (including insulin secretagogues or insulin sensitizers), meglitinides (e.g. repaglinide), sulfonylureas (e.g., glimepiride, glyburide and glipizide), biguanide/glyburide combinations (e.g., glucovance), thiozolidinediones (e.g. troglitazone, rosiglitazone and pioglitazone), PPAR-alpha agonists, PPAR-gamma agonists, PPAR alpha/gamma dual agonists, SGLT2 inhibitors, inhibitors of fatty acid binding protein (aP2) such as those disclosed in U.S. Ser. No. 09/519,079 filed Mar. 6, 2000, glucagon-like peptide-1 (GLP-1), and dipeptidyl peptidase IV (DP4) inhibitors.
Examples of suitable anti-osteoporosous agents for use in combination with the compounds of the present invention include alendronate, risedronate, raloxifene, calcitonin, non-steroidal progestin receptor agonists, RANK ligand agonists, calcium sensing receptor antagonists, TRAP inhibitors, selective estrogen receptor modulators (SERM), estrogen and AP-1 inhibitors;
Examples of suitable anti-obesity agents for use in combination with the compounds of the present invention include aP2 inhibitors such as those disclosed in U.S. Ser. No. 09/519,079 filed Mar. 6, 2000, PPAR gamma antagonists, PPAR delta agonists, and orlistat.
Examples of suitable antinflammatory agents for use in combination with the compounds of the present invention include prednisone, dexamethasone, Enbrel, cyclooxygenase inhibitors (i.e., COX-1 and/or COX-2 inhibitors such as NSAIDs, aspirin, indomethacin, ibuprofen, piroxicam, Naproxen, Celebrex, Vioxx), CTLA4-Ig agonists/antagonists, CD40 ligand antagonists, integrin antagonists, alpha4 beta7 integrin antagonists, cell adhesion inhibitors, interferon gamma antagonists, ICAM-1, tumor necrosis factor (TNF) antagonists (e.g., infliximab, OR1384), prostaglandin synthesis inhibitors, budesonide, clofazimine, CNI-1493, CD4 antagonists (e.g., priliximab), p38 mitogen-activated protein kinase inhibitors, protein tyrosine kinase (PTK) inhibitors, IKK inhibitors, and therapies for the treatment of irritable bowel syndrome (e.g., zelmac and Maxi-K openers such as those disclosed in U.S. Pat. No. 6,184,231 B1).
Example of suitable anti-anxiety agents for use in combination with the compounds of the present invention include diazepam, lorazepam, buspirone, oxazepam, and hydroxyzine pamoate.
Examples of suitable anti-depressants for use in combination with the compounds of the present invention include citalopram, fluoxetine, nefazodone, sertraline, and paroxetine.
Examples of suitable anti-hypertensive agents for use in combination with the compounds of the present invention include beta adrenergic blockers, calcium channel blockers (L-type and T-type; e.g. diltiazem, verapamil, nifedipine, amlodipine and mybefradil), diruetics (e.g., chlorothiazide, hydrochlorothiazide, flumethiazide, hydroflumethiazide, bendroflumethiazide, methylchlorothiazide, trichloromethiazide, polythiazide, benzthiazide, ethacrynic acid tricrynafen, chlorthalidone, furosemide, musolimine, bumetanide, triamtrenene, amiloride, spironolactone), renin inhibitors, ACE inhibitors (e.g., captopril, zofenopril, fosinopril, enalapril, ceranopril, cilazopril, delapril, pentopril, quinapril, ramipril, lisinopril), AT-1 receptor antagonists (e.g., losartan, irbesartan, valsartan), ET receptor antagonists (e.g., sitaxsentan, atrsentan and compounds disclosed in U.S. Pat. Nos. 5,612,359 and 6,043,265), Dual ET/AII antagonist (e.g., compounds disclosed in WO 00/01389), neutral endopeptidase (NEP) inhibitors, vasopepsidase inhibitors (dual NEP-ACE inhibitors) (e.g., omapatrilat and gemopatrilat), and nitrates.
Examples of suitable anti-platelet agents for use in combination with the compounds of the present invention include GPIIb/IIIa blockers (e.g., abciximab, eptifibatide, tirofiban), P2Y12 antagonists (e.g., clopidogrel, ticlopidine, CS-747), thromboxane receptor antagonists (e.g., ifetroban), aspirin, and PDE-III inhibitors (e.g., dipyridamole) with or without aspirin.
Examples of suitable cardiac glycosides for use in combination with the compounds of the present invention include digitalis and ouabain.
Examples of suitable cholesterol/lipid lowering agents for use in combination with the compounds of the present invention include HMG-CoA reductase inhibitors (e.g., pravastatin lovastatin, atorvastatin, simvastatin, NK-104 (a.k.a. itavastatin, or nisvastatin or nisbastatin) and ZD-4522 (a.k.a. rosuvastatin, or atavastatin or visastatin)), squalene synthetase inhibitors, fibrates, bile acid sequestrants, ACAT inhibitors, MTP inhibitors, lipooxygenase inhibitors, choesterol absorption inhibitors, and cholesterol ester transfer protein inhibitors (e.g., CP-529414).
Examples of suitable mineralocorticoid receptor antagonists for use in combination with the compounds of the present invention include spironolactone and eplerinone.
Examples of suitable phospodiesterase inhibitiors for use in combination with the compounds of the present invention include PDEIII inhibitors such as cilostazol, and PDE V inhibitors such as sildenafil.
Examples of suitable thyroid mimetics for use in combination with the compounds of the present invention include thyrotropin, polythyroid, KB-130015, and dronedarone.
Examples of suitable anabolic agents for use in combination with the compounds of the present invention include testosterone and SARMs.
Examples of suitable HIV or AIDS therapies for use in combination with the compounds of the present invention include indinavir sulfate, saquinavir, saquinavir mesylate, amprenavir, ritonavir, lopinavir, ritonavir/lopinavir combinations, lamivudine, zidovudine, lamivudine/zidovudine combinations, zalcitabine, didanosine, stavudine, and megestrol acetate.
Examples of suitable therapies for treatment of Alzheimer""s disease and cognitive disorders for use in combination with the compounds of the present invention include donepezil, tacrine, revastigmine, 5HT6, gamma secretase inhibitors, beta secretase inhibitors, SK channel blockers, Maxi-K blockers, and KCNQs blockers.
Examples of suitable therapies for treatment of sleeping disorders for use in combination with the compounds of the present invention include melatonin analogs, melatonin receptor antagonists, ML1B agonists, and GABA/NMDA receptor antagonists.
Examples of suitable anti-proliferative agents for use in combination with the compounds of the present invention include cyclosporin A, taxol, FK 506, and adriamycin.
Examples of suitable anti-tumor agents for use in combination with the compounds of the present invention include taxol, adriamycin, epothilones, cisplatin and carboplatin.
The above other therapeutic agents, when employed in combination with the compounds of the present invention, may be used, for example, in those amounts indicated in the Physicians"" Desk Reference (PDR) or as otherwise determined by one of ordinary skill in the art.
The utility of the compounds of the present invention as chemokine receptor modulators may be demonstrated by methodology known to those skilled in the art, such as the assays for CCR2 and CCR3 ligand binding, as disclosed by Ponath, et al., J. Exp. Med. 1996, 183, 2437-2448, Uguccioni, et al., J. Clin. Invest. 1997, 100, 1137-1143, and White, et al., 2000, J. Biol. Chem. 2000, 275, 36626-36631. Cell lines that express the receptor of interest include those naturally expressing the receptor, or a cell engineered to express a recombinant chemokine receptor, such as CHO, HEK-293, or RBL. The preferred compounds of the present invention have activity in binding to the CCR3 receptor in the aforementioned assays.